Background

//APOC3// loss-of-function (LOF) mutations have been associated with a lower risk of ischemic vascular disease (IVD), as well as with lower triglyceride, apolipoprotein CIII (ApoC3), and very LDL-c levels [1-4].

This study evaluated whether the low IVD risk in APOC3 LOF heterozygotes can be explained by the low plasma remnant cholesterol and low LDL-c levels. For this purpose, the levels of remnant cholesterol and LDL-c were determined in APOC3 LOF heterozygotes versus non-carriers, by means of a meta-analysis of 8 study cohorts including 137,895 individuals.

Moreover, LDL-c levels of APOC3 LOF heterozygotes were compared with those of non-carriers in 75,725 individuals in the two prospective Danish general population cohorts (Copenhagen City Heart Study and Copenhagen General Population Study), and it was assessed whether lipid-lowering therapy masked the associations of LDL cholesterol with IVD. Moreover, the fraction of the observed lower IVD and ischemic heart disease (IHD) risk associated with APOC3 LOF mutations was calculated using mediation analysis by low remnant cholesterol and low LDL-c.

Main results

In the meta-analysis, APOC3 LOF heterozygotes had 43% (95%CI: 40%–47%) lower levels of remnant cholesterol compared with non-carriers in both a fixed and in a random effects model (no heterogeneity between studies (I2=0%; P=0.92)). APOC3 LOF heterozygotes had 4% (95%CI: 1%–6%) lower levels of LDL-c compared with non-carriers in a fixed effects model and 5% (95%CI: 1%–8%) lower levels of LDL-c in a random effects model.

After correcting for lipid-lowering therapy, LOF heterozygotes in the general population had 43% (0.3 mmol/L) lower levels of remnant cholesterol (P=5×10−49) and 4% (0.1 mmol/L) lower levels of LDL-c (P=0.008) compared with non-carriers.

When excluding participants on lipid-lowering therapy at the time of lipid assessment, remnant cholesterol was 44% (0.3 mmol/L) lower (P=2×10−49), and LDL-c was 3% (0.1 mmol/L) lower (P=0.02) in LOF heterozygotes compared with non-carriers.

The mediation analysis showed that the lower levels of remnant cholesterol in LOF heterozygotes versus non-carriers mediated 37% of the lower IVD risk (P value for the indirect effect, P=6×10−37) and 54% of the lower IHD risk (P value for the indirect effect, P=1×10−37), whereas the 4% lower levels of LDL-c mediated only 1% and 2% of the lower risks.

Conclusion

The lower IVD risk in APOC3 LOF heterozygotes compared with non-carriers is largely due to the significantly lower levels of remnant cholesterol and not due to lower levels of LDL-c, and this observation was not affected by lipid-lowering therapy. These findings might be importantmay point at APOC3 and remnant cholesterol as therapeutic targets for CV prevention.